Membrane filters having a number of pores are used in a wide variety of industries such as pharmaceutical medical, electronics or food industries for sterilizing liquids, for example, whenever heat sterilization is impossible because of damage to the liquid itself. By way of example, the pore size of such membrane filter may be approximately 0.2 micrometer, and the pore density may be approximately 4.times.10.sup.9 pores per square centimeter.
One of the ultimate purposes of using this kind of membrane filter is, in the pharmaceutical industry, for example, to prevent bacteria in certain liquids from passing through the filter, i.e., from a primary side to a secondary side of the membrane filter. Therefore, to evaluate the membrane filter characteristics, a direct test which measures the ratio of bacteria in the primary side and the secondary side of the membrane filter bacteria may be employed. This test is called a bacteria challenge test in the industry. Unfortunately, the bacteria challenge test, if performed in a literal manner, is subjected to a serious drawback in that to determine the ratio of bacteria between the primary side and the secondary side of the filter requires a measurement on the secondary side of the filter. The measurement on the secondary side of the filter will introduce the danger of secondary impurities, for example, further bacteria in the already sterilized liquid. To overcome this drawback, the bacteria challenge test requires utmost care and expensive facilities to minimize the danger of introducing secondary impurities. Moreover, the bacteria challenge test requires a considerably long time. Thus, the bacteria challenge test is not practical whenever the filter has to be tested in a cost effective manner.
Therefore, various types of test systems for testing the integrity of a membrane filter using other types of test methods and without using the bacteria challenge test are known in the art. These tests are performed without measurement on the secondary side of the membrane filter to prevent the introduction of impurities on the secondary side. Then these tests are validated with respect to the bacteria challenge test if there is sufficient correlation with the bacteria challenge test.
One of the conventional membrane filter perfection test systems involves recording a curve of increasing pressure on the primary side of the membrane filter under test on a chart sheet by a pen recorder. This conventional test system operates in two modes; i.e., a bubble point mode and a pressure hold mode.
The bubble point testing is generally used in order to test the integrity of the membrane filter to verify the fact that there are no pores having a size exceeding a certain predetermined limit. In this mode, a gas pressure is provided to a wetted membrane filter to be tested at its primary side to create a pressure difference across the membrane filter. The secondary side of the membrane filter is introduced to a container filled with liquid for easy detection of bubbles. The gas pressure on the primary side is gradually increased, which causes more and more gas to permeate through the filter as the pressure keeps mounting. Initially, the rate of gas flow measured on the secondary side of the filter is proportional to the increasing gas pressure on the primary side. As soon as the rate of gas flow measured on the secondary side of the membrane filter increases at a greater rate than does the gas pressure in the primary side, as indicated by a substantial increase in the quantity of gas bubbles escaping, the bubble point has been reached. This bubble point is read from the chart of increasing pressure.
In the prior art, however, the bubble point is determined visually, which is subjective to an operator of the test system. It is especially difficult to accurately determine the bubble point when testing a large capacity membrane filter, such as a cartridge type membrane filter, since a bubble will start even in a diffusion region which is less than the bubble point. As a result, the bubble point thus determined is usually at a point which is substantially lower than the time point specified by a manufacturer. Furthermore, the curve of increasing pressure varies depending on the supply of gas from the primary side and on the flow of diffusion in the filter which may vary from filter to filter under test. Therefore, it is very difficult to accurately read the bubble point from the chart, which results in an impossible validation.
The pressure hold mode is also commonly used in evaluating the membrane filter. In this mode, a gas pressure is supplied to the primary side of a membrane filter to increase the pressure within the space in the primary side of the filter up to a predetermined pressure level. This predetermined level is within the diffusion range; i.e., the range wherein the pressure in the secondary side of the filter increases proportionally to the pressure in the primary side, and below the pressure creating the bubble point. As soon as the testing gas pressure has reached the predetermined level, the supply of gas is stopped, and any changes in the gas pressure in the primary side of the membrane filter is monitored by means of a recorder. For example, after a given initial time period, the reduction of primary side pressure is outputted as a chart which in turn is read by the operator.
In this case, only the gradual pressure reduction is indicated by the chart, irrespective of the capacity, temperature and other factors at the primary side of the membrane filter. However, the filter characteristic is susceptible to variations in these factors. Therefore, the operator must take into account the additional factors in the measuring system to compensate the test results. Even after considering these factors, in such an arrangement of the conventional test method it is considered in the industry that the test results cannot be correlated with the bacteria challenge test. Thus, the validation based on the pressure hold test is impossible.
There is further known in the prior art a diffusion flow type integrity testing system to which the pressure hold testing process is applied. The diffusion flow mode test is another kind of test widely used in the art wherein a constant pressure is applied across the wetted membrane filter and actual flow of gas on the secondary side of the membrane filter is measured. The quantity of gas diffusion is proportional to the pressure differential occurring between primary and secondary sides, and inversely proportional to the thickness of the water layer of membrane filter. For diffusion testing, the pressure applied on the inlet side has to be constant and is lower than that at which the bubble point is reached. The pressure used in this test is, for example, around 80% of that attained by the bubble point testing. The diffusion flow test is considered to be a more accurate test than the other test modes, since the test results in the diffusion flow test has a direct correlation with the bacteria challenge test.
The typical diffusion flow type perfection testing system in the prior art operates in three modes, that is, valve point mode, pressure hold mode and diffusion flow mode. Since measurements are mechanically made in the bubble point mode, less measurement errors result than with manual measurements. However, the measurement errors still remain in this type of system and are recognized to be about plus/minus 0.5 kg/cm.sup.2. As of today, since different systems were made by different manufacturers using different principles, there is an extreme confusion when membrane filters to be tested are produced by several different manufacturers. If a validation is to be visually performed while operating the machine, it is difficult to visually judge the bubble point in a cartridge-type filter which typically has a large capacity. Therefore, this bubble point mode should be exclusively used for a disc type filter which has a smaller capacity.
The pressure hold mode also is mechanically performed with fairly small measurement errors in this conventional testing system. However, the pressure hold test process itself is one that correlates with the bacteria challenge test provided by the filter manufacturers is very hardly proven in practice. Thus, the pressure hold test process also is unsuitable for validation.
The diffusion flow mode in this conventional testing system utilizes the aforementioned pressure hold test process to calculate the diffusion flow from various factors such as primary side volume metered by adding a given pressure to the primary measuring line side, pressure drop and so on. The diffusion flow mode in the conventional testing system has the following problems:
a. The diffusion flow testing process ignores an important principle that the primary pressure must be precisely maintained at a specified level. PA1 b. As the predetermined initial time is prolonged, the measurement must be performed at a pressure lower than the specified level, since there is no means provided to keep the pressure in the primary side of the filter constant. PA1 c. If the temperature in the input side of the filter under test increases, the fluid will expand and change the pressure in the primary side of the filter, resulting in an improper measurement. PA1 d. The diffusion flow testing process utilizes a standard function of mechanically determining the volume in the primary side of the membrane filter under test to calculate the diffusion flow. However, this volume measurement also creates an error. Therefore, since the measurement of the diffusion flow is made based on these erroneous measured values, the final test results have a significant inaccuracy. Furthermore, the test results have poor reproducibility.
Therefore, the conventional diffusion flow type test system for the filter integrity cannot be correlated with the bacterial challenge test, and thus validation with sufficient accuracy is not possible. Therefore, there is a need for a membrane filter test system which is capable of accurately testing the membrane filter characteristics, especially the diffusion flow characteristics so that the integrity of the filter can be accurately validated by correlation with the bacteria challenge test.